Process for the alkylation of the pyridine ring

ABSTRACT

A PROCESS IS DISCLOSED FOR ALKYLATING PYRIDINE DERIVATIVES (INCLDING PYRIDINE) AND FOR OBTAINING ALKYL- AND CYCLOALKYL-DERIVATIVES OF PYRIDINE IN WHICH THE ALKYL OF CYCLOALKYL GROUP IS IN A 2, 4 OR 6 POSITION WITH RESPECT TO THE HETEROCYCLIC NIITROGEN ATOM, WHEREIN THE PYRIDINE DERIVATIVE IS REACTED IN AN AQUEOUS SOLUTION WITH A CARBOXYLIC ACID, R-COOH, WHEREIN R IS AN ALKYL OR A CYCLOALKYL GROUP HAVING FROM 1 TO 17 CARBON ATOMS, IN THE PRESENCE OF AN ALKALINE OR AMMONIUM PERSULPHATE AND OF CATALYTIC QUANTITIES OF AG+ IONS, AT ATMOSPHERIC PRESSURE AND AT TEMPERATURES BETWEEN 40* C. AND 100* C.

United States Patent Int. Cl. C07d 31/20, 33/30, 35/22 US. Cl. 260-290 RClaims ABSTRACT OF THE DISCLOSURE A process is disclosed for alkylatingpyridine derivatives '(inclding pyridine) and for obtaining alkylandcycloalkyl-derivatives of pyridine in which the alkyl of cycloalkylgroup is in a 2, 4 or 6 position with respect to the heterocyclicniitrogen atom, wherein the pyridine derivative is reacted in an aqueoussolution with a carboxylic acid, RCOOH, wherein R is an alkyl or acycloalkyl group having from 1 to 17 carbon atoms, in the presence of analkaline or ammonium persulphate and of catalytic quantities of Ag+ions, at atmospheric pressure and at temperatures between 40 C. and 100C.

The present invention relates to a process for alkylating pyridinederivatives and, more particularly, to a process for the alkylation ofpyridine derivatives having at least one free position of the three thatare alpha and gamma with respect to the heterocyclic nitrogen atom.

The alkyl derivatives of pyridine may be profitably used in variousfields of technology. Particularly interesting is their use asintermediates for dyestuffs, weed killers and pesticides.

Various processes are already known for alkylating pyridine and itsderivatives. For example, methylation in the alpha position with respectto the nitrogen may be etfected by passing a mixture of pyridine andmethanol in a great excess over a catalyst based on Ni/Ni0 at 300 C. Thepyridines may also be methylated by means of a mixture of CO and H inthe presence of nickel at a temperature between 150 and 400 C. Moreover,it is also known to react the pyridine with carboxylic acids and withtheir lead salts in the presence of a substance having an activehydrogen as a catalyst, for instance methanol, at a temperature between80 and 120 C.

All these known processes have, however, the drawback of giving onlypoor yields of the desired alkyl derivatives.

It is an object of the present invention to provide a process for thealkylation of pyridine derivatives that shall be free of the drawbacksof the known processes and that shall at the same time be simple andcheap.

Another object of this invention is to provide a process for obtainingalkyland cycloalkyl derivatives at high yields with respect to thestarting pyridine compound.

According to this invention, a process is provided for alklating thepyridine derivatives (including pyridine itself) and for obtainingalkyland cycloalkyl derivatives having the alkyl or cycloalkyl group ina 2, 4 or 6 position with respect to the heterocyclic nitrogen atom, theprocess consisting essentially in reacting the pyridine derivative in anaqueous solution with a carboxylic acid R*COOH in which R is an alkyl ora cycloalkyl group having from 1 to 17 carbon atoms, in the presence ofan alkaline or ammonium persulphate and of catalytic quantities of Ag+ions, at atmospheric pressure and at temperatures between 40 and 100 C.For the sake of brevity, unless indicated otherwise by the context theexpressions pyridine derivatives, pyridine compounds, etc., are to betaken as including pyridine itself.

According to a preferred embodiment of the invention, the aqueousmixture of pyridine derivative, carboxylic acid and silver salt isheated up to the processing temperature and is treated with the alaklineor ammonium persulphate solution. Optionally, the mixture is refluxed inorder to complete the reaction. The time required for this operation is:between 30 and minutes. 'Ihereupon the excess carboxylic acid isrecovered from the reaction mixture by distillation or extraction with asolvent, and then is alkalinized in order to separate the mixture ofbasic products which are fractionated by rectification or by gaschromatography.

The reaction may be represented in thte following The pyridinederivative may be conveniently employed in the form of a salt with thesame carboxylic acid or by a mineral acid. The salification makes itpossible to operate in an aqueous solution with those pyridinederivatives which are only slightly soluble in Water as the free baseand to increase the reactivity of the heterocyclic ring. Thesalification by mineral acids, such as for instance, sulphuric acid, orby strong organic acids, such as halogen-acetic acids (e.g.,trichloroacetic acid), becomes necessary in the case of pyridinederivatives which are only slightly basic owing to the presence ofelectronat-tracting substituents.

As the pyridine derivative to be alkylated, one may use any compoundcontaining a pyridine ring having at least one of the three positions 2,4 and 6 free for alkylation. The pyridine derivative employed asstarting material may contain various substituents such as for instance:alkyl, cycloalkyl, halogen, cyano, alkoxy, esters (alkoxy carbonyl),amide, etc.

The pyridine ring may be joined with aromatic ring systems as, forinstance, in the derivatives of quinoline, isoquinoline, quinaldine,lepidine, acridine, benzo-isoquinoline, etc.

The carboxylic acids suitable for use in this invention are carboxylicacids -RCOOH of the saturated type in which the R group is an alkylgroup (which may be either primary, secondary or tertiary) orcycloalkyl, and containing from 1 to 17 carbon atoms.

As a source of persulphate ions, one preferably uses a persulphate ofammonium or an alkaline persulphate as, for instance, potassiumpersulphate.

The molar ratio between the pyridine derivative and the persulphatedepends on the nature both of the starting pyridine compound and of theend product that one Wishes to obtain. When positions 2,4 or 2,6 arealready substituted, only one of the reactive positions of the pyridinering (alpha and gamma with respect to the heterocyclic nitrogen atom) isfree for substitution. It is thus possible to attain without drawbackstotal conversion of the starting pyridine derivative, thereby obtaininga single end product. In such a case the ratio between the pyridinederivative and the persulphate is preferably between 1 and 0.2.

When more than one of the reactive positions 2, 4 and 6 is free, it ispossible to obtain both monoalkylated as well as dialkylated products.-In order to promote the formation of monoalkylation products and toreduce the formation of polyalkylation products, it will be necessary toachieve partial conversions of the starting product. This result may beattained by maintaining the pyridine derivative/persulphate ratiopreferably between 3 and 1, while, for obtaining dialkylation products,the

ratio between the pyridine derivative and the persulphate shallpreferably be maintained between 0.5 and 0.1.

The molar ratio between the pyridine derivative and the canboxylic acidis between 1 and 0.1. \When, for the salification, a mineral acid suchas for instance sulphuric acid is used, in general there are used from 1to 2 moles of acid per one mole of pyridine derivative.

The molar ratio between the Ag+ ion and the ammonium or alkalinepersulphate is preferably between 0.01 and 0.1. The catalytic action ofthe Ag salt is an indispensable condition for ensuring that the reactionwill result in yields that are practically acceptable; in the absence ofa catalyst the process either does not take place at all or it takesplace with very poor yields.

The following detailed working examples will serve still further toillustrate the invention.

EXAMPLE 1 A solution, containing 0.3 mole of pyridine, 0.3 mole ofsulphuric acid, 0.5 mole of propionic acid, C H -COOH, and 0.01 mole ofsilver nitrate in 70 cc. of water, was treated for 30 minutes at 70-80C. with an aqueous solution saturated with 0.1 mole of ammoniumpersulphate. This solution was then heated under reflux conditions for afurther 30 minutes and thereafter the excess propionic acid wasrecovered by distillation. The residual solution was alkalinized inorder to separate the basic products which turn out to consist ofpyridine, 2- ethyl-pyridine and 4-ethyl-pyridine.

The yield with respect to the converted pyridine is quantitative, whilethe yield with reference to the ammonium persulphate is 40% The2-ethyl-pyridine/4-ethylpyridine ratio was 1.3.

EXAMPLE 2 A solution of 0.1 mole of 4-cyano-pyridine, 0.1 mole ofsulphuric acid, 0.5 mole of propionic acid and 0.01 mole of silvernitrate was treated in the same way as in Example 1, with an aqueoussolution saturated with 0.1 mole of ammonium persulphate.

The reaction product thus obtained turned out to consist of three (3)components: 4-cyano-pyridine, Z-ethyl- 4-cyanopyridine and 2,6diethyl-4-cyano-pyridine.

The yield with respect to the converted 4-cyano-pyridine isquantitative; the yield with respect to the ammonium persulphate is 50%;while the monoethyl-derivative/diethylderivative ratio was 4.

EXAMPLE 3 This test was carried out by following the same procedure asin Example 2, but using isobutyric acid, (CH )gCH-COH, instead ofpropionic acid. Here also the yield with respect to the converted4-cyano-pyridine was quantitative, while the yield with respect to theammonium persulphate is 60%. The ratio between the 2-isopropyl-4-cyanopyridine and the 2,6-diisopropyl-4- cyano-pyridine is3.6.

EXAMPLE 4 This example was carried out by following the same proceduresas in Example 2, but using pivalic acid, (CH CCOOH, instead of propionicacid. The yield proved to be quantitative with respect to the4-cyanopyridine and 78% with reference to the ammonium persulphate. The2-t-butyl-4-cyano-pyridine/2,6-di-t-butyl-4- cyano-pyridine ratio is9.

EXAMPLE 5 This test was carried out with propionic acid as in Example 2,but using the ethyl ester of isonicotinic acid instead of the4-cyano-pyridine. A 55% yield of the 2-ethyland the2,6-diethyl-derivatives was obtained with respect to the ammoniumpersulphate, the ratio between these two derivatives being 4.8. Theyield with respect to the converted isonicotinic acid ethyl ester wasprac-, tically quantitative.

EXAMPLE 6 In this case the same procedures as in Example 2 werefollowed, but here using butyric acid,

CH (CH -COOH instead of propionic acid and ethyl isonicotinate insteadof 4-cyanopyridine. The yield with respect to the monoanddi-n-propylderivatives was 48% with respect to the ammonium persulphate,thereof consisting of the 2-propylderivative and 20% of the2,6-dipropylderivative.

EXAMPLE 7 By operating according to Example 2 with propionic acid, butusing 4,4-dipyridyl (4,4'-dipyridine) instead of 4-cyano-pyridine, theyield with respect to the ammonium persulphate was 45%. 70% of thereaction product consisted of 2-ethyl-4,4'-dipyridyl and 30% consistedof 2,2- diethyl-4,4-dipyridyl.

EXAMPLE 8 0.3 mole of 4-methylpyridine, 0.3 mole of sulphuric acid, 1mole of valeric acid, CH (CH COOH, and 0.01 mole of silver nitrate incc. of water were treated for 50 minutes at 80 C. with an aqueoussolution saturated with 0.1 mole of ammonium persulphate. At the end ofthe addition the mixture was left to rest at 80 C. for another 20minutes. It was then cooled down and then the excess of valeric acid wasextracted with ether and then recovered. Thereupon the mixture wasalkalinized and in this way there were obtained two basic products: thestarting 4-methylpyridine and 2-n-butyl-4- methylpyridine.

The yield with respect to the converted 4-methylpyridine was practicallyquantitative, while the yield with respect to the ammonium persulphatewas 43%.

EXAMPLE 9 Here Example 8 was repeated, but using 1 mole of ammoniumpersulphate per 0.1 mole of 4-methylpyridine. In this way there wasobtained 2,6-di-n-butyl-4-methylpyridine with a yield of 76% based onthe starting 4-methylpyridine.

EXAMPLE 10 The same procedures as in Example 8 operating with valericacid were followed, but using 4-methoxy-pyridine instead of4-methylpyridine. The yield in 2-n-butyl-4- methoxy-pyridine wasquantitative with respect to the converted 4-methoxy-pyridine while itwas 32% with respect to the ammonium persulphate.

EXAMPLE 11 0.1 mole of quinoline, 1 mole of butyric acid and 0.01 moleof silver nitrate in cc. of water, were treated for 1 hour at 70 C. withan aqueous solution saturated with 0.8 mole of ammonium persulphate. Inthis way a 67% yield of 2,4-di-n-propyl-quinoline was obtained based onthe quinoline used.

EXAMPLE 12 0.1 mole of Z-methylquinoline, 0.6 mole of valeric acid and0.006 mole of silver nitrate in 100 cc. of water, were treated underreflux with an aqueous solution saturated with 0.3 mole of ammoniumpersulphate for 50 minutes. In this way a 72% yield of2-methyl-4-n-butyl-quinoline was obtained based on the Z-methylquinolineused.

EXAMPLE 13 The same procedures were followed as in Example 12, using,however, cyclohexane-carboxylic acid, C H COOH instead of valeric acid.In this way a 68% yield of 2- methyl-4-cyclohexylquinoline Was obtainedbased on the Z-methylquinoline.

EXAMPLE 14 The same procedures as in Example 12 were followed here, butusing 4-methylquinoline instead of 2-methylquinoline. There was obtainedsimilarly 2-n-butyl-4-methylquinoline with a yield of 70%.

EXAMPLE 15 0.1 mole of 2-chloroquinoline, 0.1 mole of sulphuric acid,0.01 mole of silver nitrate and 1 mole of butyric acid in 150 cc. ofwater were treated for 45 minutes at 70 C. with 0.2 mole of an aqueoussolution saturated with ammonium persulphate. In this way an 83% yieldof 2- chloro-4-n-propylquinoline was obtained.

EXAMPLE 16 0.3 mole of isoquinoline, 0.3 mole of sulphuric acid, 1 moleof butyric acid and 0.01 mole of silver nitrate in 130 cc. of water weretreated for 70 minutes at 65 C. with an aqueous solution saturated withammonium persulphate. In this way an 87% yield ofl-n-propyl-isoquinoline was obtained with respect to the startingisoquinoline.

What is claimed is:

1. A process for alkylating a nitrogen heterocyclic compound to obtainalkyl and cycloalkyl derivatives thereof in which the alkyl orcycloalkyl group is in at least one of the 2, 4, and 6 positions withrespect to the heterocyclic nitrogen atom comprising reacting a pyridinecompound selected from the group consisting of pyridine, quinoline,isoquinoline, quinaldine, lepidine, acridine, benzo-isoquinoline, 4-cyanopyridine, the ethyl ester of isonicotinic acid, 4,4'-dipyridine,4-methylpyridine, 4-methoxypyridine, 2-methylquinoline,4-methylquino1ine and 2-ch1oroquinoline in a salified form in an aqueoussolution, with a carboxylic acid, RCOOH wherein R is an alkyl or acycloalcyl group having 1 to 17 carbon atoms,

in the presence of an alkaline or ammonium persulphate, and

of catalytic quantities of Ag+ ions,

at atmospheric pressure, and

at temperatures between C. and C.

2. A process according to claim 1, wherein the starting pyridinecompound is employed in the form of a salt of a mineral acid.

3. A process according to claim 1, wherein the molar ratio between thepyridine compound and the carboxylic acid varies from 1 to 0.1.

4. A process according to claim 1, wherein the alkaline persulphate ispotassium persulphate.

5. A process according to claim 1, wherein the molar ration Ag+persulphate is from 0.01 to 0.1.

6. A process according to claim 1, wherein the starting pyridinecompound has only a single reactive position and wherein the ratiobetween the pyridine compound and the ammonium persulphate is between 1and 0.2.

7. A process for obtaining mono-alkylderivatives of pyridine accordingto claim 1, wherein when the starting pyridine compound has severalreactive positions, the molar ratio between the pyridine compound andthe ammonium persulphate is between 3 and l.

8. A process for obtaining dialkyl-derivatives of pyridine according toclaim 1, wherein when the starting pyridine compound has severalreactive positions, the molar ratio between the pyridine compound andthe ammonium persulphate is between 0.5 and 0.1.

References Cited UNITED STATES PATENTS 3,428,641 2/l969 Myerly et al260290 HARRY I. MOATZ, Primary Examiner US. Cl. X.R.

260279 R, 283 R, 294.9, 295 R, 296 D, 297 R

